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Heritable Thoracic Aortic Aneurysm Genes
Study Questions:
Which genes predispose to hereditary thoracic aortic aneurysm and dissection (HTAAD)?
Methods:
The Clinical Genome Resource (ClinGen) framework was used to assess presumed gene–disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene–disease assertions were evaluated by a predefined curator–expert pair and subsequently discussed with an expert panel.
Results:
Genes were classified based on the strength of association with HTAAD into five categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. A total of 11 genes in the “definitive” and “strong” groups were designated as “HTAAD genes” (category A), eight genes were classified as unlikely to be progressive (category B), and four were classified as low risk (category C). The remaining genes were recent genes with an uncertain classification, or genes with no evidence of association with HTAAD.
Conclusions:
The ClinGen framework is useful to semi-quantitatively assess the strength of gene–disease relationships for HTAAD. The authors concluded that gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
Perspective:
Pathogenic variants in numerous genes that predispose to heritable presentations of thoracic aortic aneurysms and dissections have been identified in the past 25 years. Launched in 2013 and supported by the National Institutes of Health, ClinGen is developing authoritative central resources that define the clinical relevance of genes and variants for use in precision medicine and research. This study suggests that genetic testing may prove useful in screening patients at risk of hereditary thoracic aortic aneurysm and dissection.
Keywords: Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Genetic Testing, Risk, Secondary Prevention, Vascular Diseases
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